Device for non-thermal, electrically-induced closure of blood vessels by occlusion

ABSTRACT

Devices for the non-thermal, electrically-induced temporary or permanent closure of blood vessels. The subject devices employ pulsed electrical energy according to a defined regime to effect controlled occlusion of targeted blood vessels without hating the vessel and with minimal damage to adjacent tissue. The extent of vessel closure, i.e., temporary (vasoconstriction) or permanent (thrombosis), is controlled based on the manipulation of various parameters of the electrical stimulation regime as well as the configuration of the electrodes used to apply the regime.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/341,845, filed Dec. 30, 2011, now U.S. Pat. No. 8,235,989, which inturn is a continuation of U.S. patent application Ser. No. 11/663,672,with an international filing date of Sep. 20, 2005, now U.S. Pat. No.8,105,324, which is the national stage patent application ofInternational Patent Application No. PCT/US2005/033856, filed Sep. 20,2005, which claims the benefit under 35 USC 119(e) of U.S. ProvisionalPatent Application No. 60/612,835, filed Sep. 24, 2004, all incorporatedherein by reference in their entirety.

FEDERALLY-SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with Government support under contract EY012888awarded by the National Institutes of Health. The Government has certainrights in the invention.

BACKGROUND OF THE INVENTION

An objective of a variety of medical applications is to selectivelycompromise or destroy vascular function. One such application is thetreatment of solid tumors. It has been shown that a reduction in tumorblood flow reduces nutrients to the tumor and causes accumulation ofcatabolite products and extracellular acidification, all of which resultin a cascade of tumor cell death. Brown, J. M., Exploitation ofbioreductive agents with vasoactive drugs, In Fiedlen E. M., Fowler J.F., Hendry J. H., Scott D., eds. Proceedings of the Eight InternationalCongress on Radiation Research, Edinburg UK, Vol. 2, London, Taylor andFrancis, 1987, 719-724; Chaplin D J, Acker B., The effect of hydralazineon the tumor cytotoxicity of the hypoxic cell cytotoxin RSU-1069:evidence for therapeutic gain; Int J Radiant Oncol Biol Phys 1987, 13,579-585; Stratford I. J., Adams G. E., Godden J., Nolan J., Howells N.,Timpson N.; Potentiation of the anti-tumor effect of melphalan by thevasoactive agent, hydralazine. Br. J. Cancer 1988, 58, 122-127; DenekampJ, Hill S A, Hobson B, Vascular occlusion and tumor cell death, Eur. J.Cancer Clin. Oncol. 1983, 19, 271-275.

One approach to creating vascular dysfunction involves inducingtumor-selective thrombosis that shuts down the blood supply to the tumorcells (S. Ran, B. Gao, S. Duffy, L. Watkins, N. Rote, P. E. Thorpe,Cancer Res. 58 (1998) 4646-3653; F. Nilsson, H. Kosmehl, L. Zardi, D.Neri, Cancer Res. 61 (2001) 711-716). There are many anticancer drugsand agents which have been shown to cause such thrombosis, includingcytokines (P. L. J. Naredi, P. G. Lindner, S. B. Holmberg, U. Stenram,A. Peterson and L. R. Hafstrom, The effects of tumour necrosis factoralpha on the vascular bed and blood flow in an experimental rathepatoma, Int. J. Cancer 54 (1993), pp. 645-649; F. Kallinowski, C.Schaefer, G. Tyler and P. Vaupel, In vivo targets of recombinant humantumor necrosis factor-a: blood flow, oxygen consumption and growth ofisotransplanted rat tumours; Br. J. Cancer 60 (1989), pp. 555-560; P. G.Braunschweiger, C. S. Johnson, N. Kumar, V. Ord and P. Furmonski,Antitumor effects of recombinant human interleukin 1α in RIF-1 andPancO2 solid tumors, Cancer Res. 48 (1988), pp. 6011, 6016), serotonin,flavone acetic acid (D. J. Chaplin, The effect of therapy on tumorvascular function; Int. J. Radiat. Biol. 60 (1991), pp. 311, 325) andvinca alkaloids (S. A. Hill, L. E. Sampson and D. J. Chaplin,Anti-vascular approaches to solid tumor therapy: evaluation ofvinblastine and flavone acetic acid; Int. J. Cancer 63 (1995), pp.119-123). However, the effectiveness of many of these agents is limitedby the risk of unacceptable system toxicity (G. Sersa, M. Cemasar, C. S.Parkins and D. J. Chaplin: Tumor blood flow changes induced byapplication of electric pulses, European Journal of Cancer 35, N. 4,(1999) pp. 672-677), among other factors.

Various other types of therapies have also been shown to affect somedegree of vascular dysfunction in tumors, including hyperthermia (C. W.Song, Effect of local hyperthermia on blood flow and microenvironment,Cancer Res. 44 (1984), pp. 4721-4730), photodynamic therapy (V. H.Fingar and B. W. Henderson, Drug and light dose dependence ofphotodynamic therapy: a study of tumour and normal tissue response.Photochem. Photobiol. 46 (1987), pp. 837-841) and high-energy shock wavetherapy (F. Gamarra, F. Spelsberg, G. E. H. Kuhnle and A. E. Goetz,High-energy shock waves induce blood flow reduction in tumors, CancerRes. 53 (1993), pp. 1590-1595). However, complete and permanenthemostasis has not yet been achieved by these methodologies. Mechanicalclamping of the tumor-supporting vasculature has also been proposed(Denekamp J, Hill S. A., Hobson B., Vascular occlusion and tumor celldeath, Eur. J. Cancer Clin. Oncol. 1983, 19, 271-275), however, suchtechnique may be impractical due to the extremely twisted and branchednature of tumor vasculature.

Another application involving the selective destruction of vascularfunction is in the treatment of cutaneous vascular disorders, such astelangiectasia (commonly known as “spider veins”) and in the removal ofcutaneous vascular lesions, e.g., capillary hemangiomas (such ascafe-au-lait spots and port wine stains). These conditions all involvedilated or engorged capillaries in the skin. While not often of physicalconcern, they can be unsightly and cause emotional distress to thepatient.

The most common treatment used for cutaneous vascular lesions issclerotherapy, which entails the intravascular injection of one of avariety of agents into the abnormal blood vessels. The injectedsubstance injures the interior walls of the capillary causing it toshrink or disappear. Unfortunately, this treatment can be painful, onlypartially effective, and usually requires about one to two months beforeimprovement can be seen. In addition, undesirable side effects canoccur, such as echymotic or hyperpigmented marks, which may take monthsto completely fade away.

Other treatments such as freezing, surgery, radiation, phototherapy andlaser therapy have also been employed for subcutaneous and cutaneousvascular conditions. Of these, the use of lasers has been the mostsuccessful as the destruction of the offending capillaries is achievedwith the least amount of damage to the overlying skin. However, lasertherapy is not without its shortcomings. The blood hemoglobin absorbsthe laser light and the resulting hyperthermia leads to coagulation ofthe blood within the vessels in the surface layer of the skin. Where theaffected skin area is relatively deep, the more superficial capillariesabsorb the majority of the light energy and the remaining energy isinsufficient to effectively treat the deeper vessels (referred to as“shadowing”). This problem can be solved to some degree by use of lessabsorbent wavelengths, however, this is at the sake of a reduced abilityto localize heat, which may necessitate longer treatments and/ormultiple treatments which are both expensive and time-consuming.Additionally, laser therapy does not work as well with patients having adarker skin pigment as the epidermal melanin absorbs a significantportion of the light to which it is exposed, thus, reducing the amountof light that is able to reach the blood. The increase in the intensityof the laser required to compensate for interference from tissue andmelanin may lead to thermal injury of the skin and to post-inflammatorypigment changes.

Many recent improvements in electrosurgical technology, particularly inbipolar electrosurgical devices, have made it easy to use in surgicaland other therapeutic settings. Ostensibly, electrosurgery may be aviable alternative to the above-described modalities for treating tumorsand cutaneous and subcutaneous vascular disorders. However, currentelectrosurgical devices and procedures are based on the thermaldenaturation and coagulation of tissues and still suffer fromsignificant thermal damage to surrounding tissue, and an inability toaccurately control the depth of necrosis in the tissue being treated.Additionally, the application of current to tissue results inelectrochemical reactions which lead to the accumulation of toxicproducts on the electrodes that may cause cytolysis of the surroundingtissue (Peterson H. I., Tumor Blood Circulation: Angiogenesis, VascularMorphology and Blood Flow of Experimental and human tumors, Florida, CRCPress, 1979, 1-229). In addition, hydrolysis on the electrodes emitsgases which may interfere with current transmission, making thetreatment unpredictable and unstable (S. Guarini, A Highly ReproducibleModel of Arterial Thrombosis in Rats, Journal of Pharmacological andToxicological Methods, 35 (1996) pp 101-105). These shortcomings areparticularly significant in applications in which the target area isextremely small, e.g., capillary vessels having diameters in the rangefrom about 10 to about 100 μm.

Accordingly, there is still a need for improved methodologies forcreating hemostasis within blood vessels without causing damage toadjacent tissue. In particular, there is a need for a more effective andsafe way to treat solid tumors and cutaneous and subcutaneous vasculardisorders.

SUMMARY OF THE INVENTION

The present invention provides methods and devices for the non-thermal,electrically induced temporary or permanent closure of blood vessels.The subject methods and devices employ short pulses of electricalcurrent according to a defined regime to effect a controlled occlusionof targeted blood vessels without heating the vessel and with minimalelectrochemical damage to adjacent tissue. The extent of vessel closure,i.e., temporary (vasoconstriction) or permanent (occlusion), iscontrolled based on the manipulation of various parameters of theelectrical stimulation regime as well as the configuration of theelectrodes used to apply the regime.

The subject methods include the application of short-duration electricalpulses to induce an electrical field to the targeted blood vessel(s) andthereby cause the occlusion of the blood vessel(s). The treatmentregimes employed in the subject methods may be optimized for aparticular application by the selection of various parameters of thetreatment regime. These parameters include but are not limited to pulseduration, the polarity of the pulses, pulse frequency, the frequency ofthe pulses within a burst, the duration of a burst, the duration of thetreatment regime, and the number of sets of bursts within a treatmentregime.

The subject devices include an electrode configuration having a geometryselected specifically for application to target tissue region, where thedepth and surface area of the affected tissue region are considerationsdictating an optimal electrode configuration. In one variation, an arrayof active electrodes is provided with a larger return electrode situatedremotely from the active electrodes. In another variation, each activeelectrode is provided with a surrounding return electrode.

One object of the invention is to selectively induce hemostasis withinblood vessels by creating thrombosis within the vessels with minimalside effects, fewer steps and less discomfort to the patient than hasheretofore been possible.

The present invention is useful in treating solid tumors, aneurysms,vascular malformations, arteriovenous fistulas (e.g., carotid-cavernous,vertebral), internal arterial bleeding sites, damaged vessels followingtrauma and the like, and cutaneous and subcutaneous vascular conditions,such as port wine stains.

These and other objects, advantages, and features of the invention willbecome apparent to those persons skilled in the art upon reading thedetails of the invention as more fully described below.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is best understood from the following detailed descriptionwhen read in conjunction with the accompanying drawings. It isemphasized that, according to common practice, the various features ofthe drawings are not to-scale. On the contrary, the dimensions of thevarious features are arbitrarily expanded or reduced for clarity.Included in the drawings are the following figures:

FIGS. 1A and 1B illustrate cross-sectional and top views, respectively,of an embodiment of an electrode configuration suitable for use with thepresent invention.

FIGS. 2A and 2B illustrate cross-sectional and top views, respectively,of another embodiment of an electrode configuration suitable for usewith the present invention.

FIGS. 3A and 3B illustrate cross-sectional and top views, respectively,of another embodiment of an electrode configuration suitable for usewith the present invention.

FIGS. 4A and 4B illustrate cross-sectional and top views, respectively,of another embodiment of an electrode configuration suitable for usewith the present invention.

FIG. 5 is a graph an exemplary waveform of a treatment regime of thepresent invention.

FIGS. 6A-6C illustrate videoscopic views of a chorioallantoic membrane(CAM) upon which an experiment employing the devices and methods of thepresent invention was conducted

FIGS. 7A-7C illustrate histological views of a blood vessel in the CAMof FIGS. 6A-6C.

DETAILED DESCRIPTION OF THE INVENTION

Before the subject devices, systems and methods are described, it is tobe understood that this invention is not limited to particularembodiments described, as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting, since the scope of the present invention will be limited onlyby the appended claims.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “apulse” includes a plurality of such pulses and reference to “theelectrode” includes reference to one or more electrodes and equivalentsthereof known to those skilled in the art, and so forth.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimits of that range is also specifically disclosed. Each smaller rangebetween any stated value or intervening value in a stated range and anyother stated or intervening value in that stated range is encompassedwithin the invention. The upper and lower limits of these smaller rangesmay independently be included or excluded in the range, and each rangewhere either, neither or both limits are included in the smaller rangesis also encompassed within the invention, subject to any specificallyexcluded limit in the stated range. Where the stated range includes oneor both of the limits, ranges excluding either or both of those includedlimits are also included in the invention.

All publications mentioned herein are incorporated herein by referenceto disclose and describe the methods and/or materials in connection withwhich the publications are cited. The publications discussed herein areprovided solely for their disclosure prior to the filing date of thepresent application. Nothing herein is to be construed as an admissionthat the present invention is not entitled to antedate such publicationby virtue of prior invention. Further, the dates of publication providedmay be different from the actual publication dates which may need to beindependently confirmed.

Generally, the methods of the present invention include the applicationof an electrical current stimulation regime having a pulsatile waveformto a target tissue area or one or more targeted blood vessels and whichproduces an electric field in the targeted area sufficient to causeocclusion of the target vessels.

The pulsatile waveform includes current pulses of monophasic orbi-phasic (alternating) polarities that produce the desired occlusion inthe target vessel(s) while maintaining the target tissue at acceptabletemperatures, i.e., below the temperature at which irreversible tissuedestruction occurs. Accordingly, the average temperature rise in thetreated tissue area during the electrical stimulation procedure is nomore than about 10° C. The pulsed electrical treatment with bi-phasicpulses according to the subject methods also avoids irreversibleelectrochemical reactions on the electrodes, thereby reducing tissuedamage.

In certain variations, the treatment regime includes the application ofone or more pulses or bursts of pulses. Typically, the regime involvesat least two pulses or bursts, and more typically, it applies aplurality of pulses or bursts in a periodic fashion for several minuteswhere permanent or irreversible occlusion of the target blood vessel(s)is desired.

The necessary scope or depth of the electric field to be applied to thetarget area depends at least in part on the depth of the targeted bloodvessels from the tissue or skin surface against which the electrodes arecontacted. Where only shallow penetration of the electric field isrequired over a relatively large surface area, for example when treatingcutaneous vascular disorders, a preferable electrode configuration orgeometry includes either a sequentially-activated array of small activeelectrodes with a larger remotely-positioned return electrode, or anarray of active electrodes each of which is surrounded by theclosely-spaced return electrodes (bipolar geometry). In the secondvariation, the electrodes in the array may be activated simultaneously.

An example of such an electrode configuration suitable for use with thepresent invention is illustrated in FIGS. 1A and 1B. Electrode assembly2 includes a planar (two-dimensional) array of active electrodes 4distributed over a distal contact surface of a probe (not shown) mountedon an insulating substrate or support material 8, such as siliconeelastomer. Active electrodes 4 are in the form of isolated dots orpoints concentrically surrounded by but spaced from a single, largerreturn electrode 6 extending over substrate 8. Another electrodeconfiguration suitable for use with the present invention is illustratedin FIGS. 2A and 2B. Here, electrode assembly 10 includes an array ofparallel lines or strips of active electrodes 12 and return electrodes14 mounted on where the active and return electrodes are interspacedwith each other in an alternating fashion.

With a bipolar configuration (FIGS. 1 and 2), the interspacedrelationship of the active and return electrodes of electrode assemblyallows for parallel, i.e., simultaneous, activation of the electrodes.The electric field resulting from voltage applied between the active andreturn electrodes is concentrated between the two, as indicated byelectric field distribution 7. By adjusting the distance or gap betweenthe active and return electrodes, the penetration depth of the electricfield can be adjusted, i.e., the greater the gap, the greater thepenetration depth.

FIGS. 3A and 3B illustrate another electrode assembly 20 having an arrayof active electrodes 22 mounted on an insulated substrate or supportmaterial 24. Similar to the electrode assembly of FIGS. 1A and 1B,active electrodes 22 have a dot or point configuration. FIGS. 4A and 4Billustrate another electrode assembly 30 having an array of activeelectrodes 32 mounted on an insulated substrate or support material 24.Similar to the electrode assembly of FIGS. 2A and 2B, active electrodes32 are provided in the form of parallel strips of lines. Unlike theembodiments of FIGS. 1 and 2, however, the return electrode (not shown)is provided remotely, from the respective active electrode arrays, suchas proximally along the probe shaft or remotely from the probealtogether With these arrangements, the active electrodes may beactivated sequentially and independently of each other, where one ormore active electrodes are selectively activated to control penetrationdepth of the field into tissue. When electrodes in the array areactivated simultaneously the whole array works as a single largeelectrode, thus resulting in very deep penetration of the electricfield—on the order of the size of the array. The sequential activationof the electrodes allows for limiting the penetration depth of electricfield 26 and 36 to the width of one electrode in the array, as shown inFIGS. 3 and 4, respectively. Since the penetration depth of the electricfield depends on the size and separation between the electrodes it maybe selected and adjusted as necessary to obtain the desired treatmentarea.

The active electrodes of the electrode assemblies of the presentinvention may be electrically isolated from each other where eachelectrode is connected to a separate power source that is isolated fromthe other electrode terminals. The isolated power sources for eachindividual electrode may be separate power supply circuits, or may be asingle power source which is connected to each of the electrodes throughindependently actuatable switches. In an alternate embodiment, theelectrodes may be connected to each other at either the proximal ordistal ends of the probe to form a single wire that couples to a singlepower source.

Various parameters of the treatment regime are selected based on thediameter(s) of the vessels to be occluded, the extent of occlusion(partial occlusion, i.e., vasoconstriction, or complete occlusion, i.e.thrombosis) and the duration or reversibility of the occlusion. Suchparameters include pulse duration, burst duration where a burst includesa plurality of pulses, pulse frequency within a burst, burst frequencyor repetition rate, the total treatment time where the treatmentduration includes a plurality of bursts, and the electric fieldintensity or current density. For applications involving blood vessels,both arteries and veins, having diameters in the range from about 0.05to about 5 mm, typical value ranges for these parameters are as follows:

Pulse duration from about 0.01 μs to about 1 ms Burst duration fromabout 0.2 μs to about 2 ms Pulse frequency within a burst from about 0.1to about 10 MHz Burst (or pulse) repetition rate from about 0.01 toabout 100 Hz Treatment duration from about 0.1 μs to about 1 hr Electricfield from about 7 to about 35000 V/cm Current density from about 0.1 toabout 500 A/cm2

The methods of the present invention involve electrically-inducedocclusion, either partial or complete, of blood vessels in tissue. Oneor more active electrode(s), such as described above, are positioned inclose proximity to a target region of the skin above the targeted bloodvessel. The electrode assembly may be positioned on the external surfaceof the skin, or may be introduced through a percutaneous penetration inthe outer skin surface to the targeted blood vessel(s). In the latterembodiment, the percutaneous penetration may be formed by advancing oneor more needle electrodes through the outer surface of the skin to thetarget region of the vessel. Alternatively, an electrosurgicalinstrument may be introduced into the patient's vasculature and advancedtransluminally to a target site. The subject methods may further beperformed using traditional open surgery techniques.

Once the electrodes are positioned, a sufficient voltage, e.g. fromabout 1 to about 300V, is applied to the electrodes in a pulsedwaveform. A resulting pulsed, monophasic or biphasic current travelsthrough the tissue and an associated electric field develops at adesired tissue depth, typically from about 0.1 to about 5 mm from thecontacted surface, where the depth is from about 0.1 to about 5 mm underthe surface of the skin when treating vascular conditions of the skin,or from about 1 to about 50 mm from the contacted tissue surface whentreating solid tumors.

The applied electric current produces heat energy (Joules) in thephysiological medium and tissue. Electric field E applied during thetime t in the medium with resistivity σ will result in temperature riseΔT=t·E²/(ρσc), where ρ is tissue density and c is heat capacitance. Forexample, with t=1 μs and E=20 kV/cm only a very slight temperaturechange ΔT=1.4° C. occurs during the pulse, within the treated tissueregion, which is far below that which would cause thermal damage.Characteristic diffusion time for electrodes of 1 mm in diameter isabout 1 second, thus with pulse repetition rate of 0.1 Hz the averagetemperature rise will be on the order of ΔT_(AVE)=0.14° C. Thus, nothermal damage occurs with a single pulse or with a sequence of pulses.

The current waveform has a pulse duration and frequency within theranges provided above. The resulting electric field or current densityof the pulsed waveform is sufficient to induce a constriction andocclusion (thrombosis) of the blood vessel, so that blood flow throughthe vessel is restricted or completely interrupted. The duration of theelectrical stimulation treatment will depend on the size and density ofthe target vascular area.

In order to further ensure that surrounding tissue and the untargetedportions of the blood vessels are not affected or damaged by theelectrical stimulation, the subject methods optionally provide for thetopical application of one of various protective agents or medicationsto areas of the patient's skin or tissue surfaces. These agents ormedications fall generally within the category of calcium blockers whichproduce blockages in the ion channels in the cell membranes and/or themembranes of cellular organelles exposed to the agent. The calciumblockers were found to reduce or completely prevent theelectrically-induced vasoconstriction. For cutaneous or subcutaneousvascular conditions, such as Port Wine Stains, the calcium blocker agentcan be applied to the skin surrounding the boundaries of the vascularlesion prior to electrical stimulation. As such, the cutaneous andsubcutaneous vessels in the agent-covered areas remain unaffected by theelectrical stimulation. For solid tumor applications, the calciumblocker agent is applied to the skin above the location of the tumorsuch that only the tumor is affected by the applied electrical energyand not the skin or tissue there between. Thus, the calcium blockeragents can be used in conjunction with the electrical stimulationregimes of the present invention to chemically regulate the extent ofvasoconstriction. An example of calcium blockers suitable for use withthe present invention includes but is not limited to tetraethylammonium.The concentration of the agent used is usually in the range from about1×10⁻⁵ to about 1×10⁻³ mol/L, where an exemplary concentration fortetraethylammonium is about 2.5×10⁻⁴ mol/L.

EXAMPLE

The following example is put forth so as to provide those of ordinaryskill in the art with an exemplary disclosure and description of how toemploy the present invention, and is not intended to limit the scope ofwhat the inventor regards as his invention nor is it intended torepresent that the experiments below are all or the only experimentsperformed. Efforts have been made to ensure the accuracy of the data,however, some experimental errors and deviations should be accountedfor.

A chorioallantoic membrane (CAM) of a chicken embryo 17 days into theincubation cycle was used for performing the experiments. Various bloodvessels (three arteries and three veins) of the CAM were selected fortreatment, where the vessels were of varying diameters. An electrode of2 mm in length, 300 μm in width and 50 μm in thickness was used. Usingthe electrode assembly, a selected minimum threshold voltage of 100 Vwas applied in biphasic (having positive and negative phases in thepulse) pulses to the targeted vessels The total biphasic pulse durationwas 1 μs, the duration of each phase was 500 ns, the repetition rate was1 Hz (1 second between the pulses) and the total treatment time was 3minutes, at which point thrombi had formed within each of the targetedvessels. As the vessels were all approximately at the same depth beneaththe exposed surface of the membrane, the threshold electric field valuesachieved were the same for identical applied voltages. Stasis wasachieved for each vessel without thermal damage to adjacent tissue anduntargeted vessels. The vessel diameter, threshold voltage and electricfield, and voltage and electric field values at complete stasis aresummarized in the table below.

Threshold Vessel Threshold Electric Electric Field Vessel DiameterVoltage Field Voltage at at Stasis Type O.D. (μm) (V) (kV/cm) Stasis (V)(kV/cm) Artery 75 80 7.3 90 8.2 Artery 100 80 7.3 170 15.5 Artery 225 807.3 300 27.4 Vein 75 60 5.5 90 8.2 Vein 150 60 5.5 120 10.9 Vein 275 605.5 250 22.8

FIGS. 6A-6C are videoscopic views demonstrating the clinical appearanceof the vasoconstriction and thrombosis. FIGS. 7A-7C illustrate thehistological views of a CAM vessel upon which the above experiment wasperformed. FIGS. 6A and 7A illustrate the appearance of the targetedvessel prior to treatment according to the subject methods. FIGS. 6B and7B illustrate the vessel as it undergoes vasoconstriction duringapplication of the electrical stimulation protocol. FIGS. 6C and 7Cillustrate the vessel after thrombosis is achieved at a targeted area ofthe vessel with no noticeable damage to the tissue surrounding thetargeted vessel.

The present invention further includes the provision of the subjectdevices in the form of a kit which may include two or more of the abovedescribed electrode assemblies and various probes to be used with thecatheter assemblies. The electrode assemblies may vary in size and/orgeometry which may be selected for the application at hand. The kits mayfurther include other instruments to facilitate the performance of thesubject methods, including but not limited to catheter-based instrumentsto facilitate percutaneous delivery of the electrode assembly to atarget site. The kits may further include prepackaged dosages of one ormore of the above-described medications. Additionally, the kits mayinclude instructions for using the various devices and/or medications toperform the subject methods.

The preceding merely illustrates the principles of the invention. Itwill be appreciated that those skilled in the art will be able to devisevarious arrangements which, although not explicitly described or shownherein, embody the principles of the invention and are included withinits spirit and scope. Furthermore, all examples and conditional languagerecited herein are principally intended to aid the reader inunderstanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentinvention, therefore, is not intended to be limited to the exemplaryembodiments shown and described herein. Rather, the scope and spirit ofpresent invention is embodied by the appended claims.

1. A device for occlusion of targeted blood vessels in a patient,comprising: an electric probe having an assembly of electrodesconfigured for contacting a tissue proximate the targeted blood vessels;wherein the targeted blood vessels have at least one of: an aneurysm, anarteriovenous fistula, an internal bleeding site, or define a port winestain; and a pulse generator electrically coupled to the electric probeand configured to apply electric pulses to the tissue, wherein theelectric pulses are adapted to cause an average temperature rise in thetissue of no more than about 10° C. and no irreversible reaction on theelectrodes and thereby cause the irreversible occlusion of the targetedvessels without thermally coagulating the blood vessels and with nothermal damage to the tissue.
 2. The device of claim 1, wherein theelectrode assembly comprises an array of active electrodes and a largerreturn electrode situated remotely from the active electrodes.
 3. Thedevice of claim 2, wherein active electrodes are configured to beactivated sequentially.
 4. The device of claim 1, wherein the electrodeassembly comprises an array of active electrodes surrounded by one ormore return electrodes.
 5. The device of claim 4, wherein the activeelectrodes are configured to be activated simultaneously.
 6. A kitcomprising: the device of claim 1; and at least one dosage of a calciumblocker configured for topical application.
 7. The kit of claim 1,further comprising: instructions for using the device to selectivelyconstrict one or more of the targeted blood vessels within a patient. 8.A device for occlusion of targeted blood vessels in a patient,comprising: an electric probe having an assembly of electrodesconfigured for contacting a tissue proximate the targeted blood vessels;and a pulse generator electrically coupled to the electric probe andconfigured to apply electric pulses to the tissue, wherein the electricpulses are adapted to cause an average temperature rise in the tissue ofno more than about 10° C. and no irreversible reaction on theelectrodes, and thereby cause a reversible occlusion of the targetedvessels without thermally coagulating the blood vessels and with nothermal damage to the tissue.